The purpose of this study is to clarify the relationship between arachidonic acid (AA) metabolites, renal disease and immune function in autoimmunity by modifying one of these elements at a time and studying the impact upon the others. Since renal macrophage/accessory cell Ia antigen expression and thromboxane (TXA2) synthesis are the major features which are linked to each component, studies shall focus upon understanding their interrelationship. By using the MRL-lpr mice in which autoimmunity is regulated by a single gene (1pr), kidneys are examined before and after renal dysfunction, compared with congenic MRL-++ mice lacking the lpr gene and with other strains with lpr, but free of renal disease. NZBxW F1 hybrid mice will be evaluated and compared with the MRL strain to identify features common to autoimmunity. Studies plan to determine whether TXA2 causes renal injury to lupus nephritis and whether other AA metabolites influence the expression of this disease. Using experimental procedures to reduce TXA2 synthesis specifically and other AA metabolites, we will analyze the effects on renal disease and specific immune functions characteristic of lupus. Experiments will concentrate on determining whether renal TXA2 is generated by cells in the circulation or within intrinsic renal cells. Cultured cells from glomeruli of mice with lupus nephritis will be stimulated with lymphokines, monokines and immune complexes and examined for TXA2 synthesis, TXA2, receptor expression, and PGE2, PGI2 and the 5 lipoxygenase products. By selecting murine strains with and without the lpr gene before and after nephritis, kidneys will be evaluated for macrophages and surface Ia antigen expression in glomerular cell suspensions and homogeneous cell cultures using dual labeling fluorescence techniques and multiparametric flow cytometry. This information will be correlated with the ability of each cell type to synthesize AA metabolites. In the final section, proven and new experimental immunologic tools (lymphokine and monoclonal antibodies for Ia and IL 2 receptors) will be given to alter renal disease and we will evaluate the impact on immune abnormalities characteristic of lupus and AA metabolite production. Thus, the proposed studies have a basic and applied significance. These studies are designed to further our understanding of the pathogenesis and treatment of lupus nephritis and other forms of renal disease.